A primary goal of the Mackall laboratory is development of immune based therapies for childhood cancer. Because standard upfront therapies for childhood cancers often induce a very good partial remission or complete remission, even in incurable disease, we have focused greatly on delivering immune based therapy as a consolidative treatment. To this end, we seek to integrate immune based therapies into the existing therapeutic armamentarium, by administering immunotherapy immediately following completion of standard multiagent chemotherapy. We hypothesize that immunotherapy will be more effective against minimal residual cancer than against bulky tumors due to a more favorable immune cell:tumor cell ratio and the absence of an organized immunosuppressive microenvironment. Previous work from the Mackall laboratory directly demonstrated that immune responses are more effective at eradicating minimal residual neoplastic disease that primary bulky tumor (Merchant, Cancer Immun and Immunoth, 2006). Furthermore, our expertise in the biology of T cell depletion provides us with unique insights regarding how best to deliver immune based therapy following cytotoxic chemotherapy, which the vast majority of childhood cancer patients receive as part of standard therapy. Because our translational research program has targeted childhood sarcomas, it is critical that we maintain an active clinical program in this arena, which provides the necessary referral network to conduct clinical trials in pediatric cancers and the necessary biologic specimens to conduct studies of relevance to human disease. Results of our first and second generation studies of consolidative immunotherapy were previously published (Medical and Pediatric Oncology 2002, Nature Medicine 2005 and Clin Canc Res 2008). During FY2010 we continued accrual of patients with pediatric sarcomas on a trial of immune based therapy initiated in 2008. The trial directly translates our basic research by administering dendritic cell based tumor vaccines to patients with high-risk pediatric sarcomas rendered lymphopenic by standard chemotherapy. Patients receive autologous lymphocytes depleted of suppressive T cells as a means to enhance immune responses. During FY10, we also incorporated rhIL7 into this therapy, representing the first use of this agent in children. A total of 26 patients have been accrued and 10 patients have completed immunotherapy. This trial incorporates a helper antigen, keyhold limpet hemocyanin (KLH), to augment immune responses. Results thus far demonstrate vigorous immune responses to KLH but limited responses to the tumor lysate. Other accomplishments include the completion of accrual to a clinical trial of testing monoclonal antibodies to anti-TRAIL receptor 2. While there were no objective responses in this Phase I study, we did see an interesting rate of stable disease and evidence for clinical activity in hepatoblastoma, as well as data to suggest that anti-TRAIL receptor therapies may syngergize with radiation therapy. These results were presented at ASCO in 2010 and are currently being prepared for publication. In addition, we are conducting the only Phase I study of anti-CTLA4 in pediatrics, targeting patients with pediatric melanoma. Finally, we initiated a study tumor respository study to acquire tissues from pediatric patients and conduct genomic analyses, which will be a general service to the pediatric oncology community.